1. Mouse and Drosophila models of AD
Mouse and Drosophila models of AD. (A) (i) Murine models of AD are typically generated by the overexpression of disease-linked variants of human proteins, such as APP, the active subunit of γ-secretase (PSEN1) and/or tau.
Mouse and Drosophila models of AD. (A) (i) Murine models of AD are typically generated by the overexpression of disease-linked variants of human proteins, such as APP, the active subunit of γ-secretase (PSEN1) and/or tau. The APOE knockout (KO) mouse also serves as a model of AD. (ii) Tg2576 (Hsiao et al., 1996) and TgCRND8 (Janus et al., 2000) mice express mutants of human APP that are cleaved by β- and γ-secretases to generate neurotoxic Aβ peptides. The APP transgene can be combined with other transgenes, as for example in the 3×TgAD mouse, which carries human disease-linked variants of APP (the so-called Swedish mutation), PSEN1 and tau (Oddo et al., 2003). This triple transgenic mouse replicates many features of AD (see Aβ plaques and tau tangles in iii, arrows). High power views of Gallyas silver-stained Aβ plaques (image credit: Jensflorian, Wikimedia Commons) and Gallyas silver-stained tau tangles (image credit: Patho, Wikimedia Commons). Tauopathy, a neurodegenerative disorder related to AD, can be modelled in P301L (Lewis et al., 2000) and R406W (Tatebayashi et al., 2002) tau transgenic mice. APOE KO mice might replicate some features of AD, such as amyloid and tau deposition, and exhibit metabolic and circadian abnormalities (Zhou et al., 2016), although these observations require independent replication. The 3×TgAD mice also exhibit mild circadian dysfunction, including differences in the amplitude (iv) and timing (v) of body temperature oscillations (Knight et al., 2013). (B) (i) Fruit fly models of Aβ toxicity are typically generated by expressing the Aβ peptide downstream of a secretion signal peptide (Crowther et al., 2005; Finelli et al., 2004; Iijima et al., 2004). (ii) In these models, intraneuronal and extracellular deposits of Aβ are visible in transverse sections of fly brain stained with anti-Aβ antibodies (red, cell nuclei in blue; reproduced with permission from Ott et al., 2015). Scale bar: 200 µm. (iii) The expression of toxic forms of the Aβ1-42 peptide, such as the E22G Arctic variant, elicit progressive sleep deficits as evidenced by the loss of the rhythmicity in the actimetry traces as the transgenic flies age (reproduced with permission from Chen et al., 2014). Wild-type flies retain a youthful pattern of behaviour, resembling the 2-12 days data, at all time points shown.
Ruchi Chauhan et al. Dis. Model. Mech. 2017;10:
© Published by The Company of Biologists Ltd